Choroidal neovascularization can lead to hemorrhage and fibrosis, with resulting visual loss in a number of conditions of the eye, including, for example, age-related macular degeneration, ocular histoplasmosis syndrome, pathologic myopia, angioid streaks, idiopathic disorders, choroiditis, choroidal rupture, overlying choroid nevi, and certain inflammatory diseases. One of the disorders, namely, age-related macular degeneration (AMD), is the leading cause of severe vision loss in people aged 65 and above (Bressler et al. (1988) SURV. OPHTHALMOL. 32, 375–413, Guyer et al. (1986) ARCH. OPHTHALMOL. 104, 702–705, Hyman et al. (1983) AM. J. EPIDEMIOL. 188, 816–824, Klein & Klein (1982) ARCH. OPHTHALMOL. 100, 571–573, Leibowitz et al. (1980) SURV. OPHTHALMOL. 24, 335–610). Although clinicopathologic descriptions have been made, little is understood about the etiology and pathogenesis of the disease.
Dry AMD is the more common form of the disease, characterized by drusen, pigmentary and atrophic changes in the macula, with slowly progressive loss of central vision. Wet or neovascular AMD is characterized by subretinal hemorrhage, fibrosis and fluid secondary to the formation of choroidal neovasculature (CNV), and more rapid and pronounced loss of vision. While less common than dry AMD, neovascular AMD accounts for 80% of the severe vision loss due to AMD. Approximately 200,000 cases of neovascular AMD are diagnosed yearly in the United States alone.
Currently there is no treatment for dry AMD. Until recently, laser photocoagulation has been the only therapy available for selected cases of neovascular AMD. Unfortunately, the majority of patients with neovascular AMD do not meet the criteria for laser photocoagulation therapy. Approximately 85% of patients with neovascular AMD have poorly defined, occult, or relatively extensive subfoveal choroidal neovascularization, none of which is amenable to laser therapy. In addition, laser photocoagulation relies on thermal damage to the CNV tissue, which damages the overlying neurosensory retina with consequent loss of visual function. Laser photocoagulation also is plagued by recurrences that occur in approximately 50% of cases.
Photodynamic therapy (PDT) has shown promising results as a new treatment for removing unwanted CNV and for treating neovascular AMD (Miller et al. (1999) ARCHIVES OF OPHTHALMOLOGY 117: 1161–1173, Schmidt-Erfurth et al. (1999) ARCHIVES OF OPHTHALMOLOGY 117: 1177–1187, TAP Study Group (1999) ARCHIVES OF OPHTHALMOLOGY 117: 1329–45, Husain et al. (1999) PHILADELPHIA: MOSBY; 297–307). PDT involves the systemic administration of a photosensitizer or PDT dye (photosensitizer) that accumulates in proliferating tissues such as tumors and newly formed blood vessels; followed by irradiation of the target tissue with low-intensity, non-thermal light at a wavelength corresponding to the absorption peak of the dye (Oleinick et al. (1998) RADIATION RESEARCH: 150: S146–S156). Excitation of the dye leads to the formation of singlet oxygen and free radicals-better known as reactive oxygen species which cause photochemical damage to the target tissue (Weishaupt et al. (1976) CANCER RES. 36: 2326–2329).
Studies using PDT for the treatment of CNV have demonstrated that, with the proper treatment parameters of photosensitizer dose, laser light dose, and timing of irradiation, relative selective damage to experimental CNV can be achieved, sparing retinal vessels, large choroidal vessels, and with minimal changes in the neurosensory retina (Husain et al. (1996) ARCH OPHTALMOL. 114: 978–985, Husain et al. (1997) SEMINARS IN OPHTHALMOLOGY 12: 14–25, Miller et al. (1995) ARCH OPHTHALMOL. 113: 810–818, Kramer et al. (1996) OPHTHALMOLOGY 103(3): 427–438). Moreover, a PDT-based procedure using a green porphyrin dye recently has been approved in a variety of countries for use in the treatment of neovascular AMD.
During clinical studies, however, it has been found that recurrence of leakage appears in at least a portion of the CNV by one to three months post-treatment. Increasing photosensitizer or light doses do not appear to prevent this recurrence, and can even lead to undesired non-selective damage to retinal vessels (Miller et al. (1999) ARCHIVES OF OPHTHALMOLOGY 117: 1161–1173). Several multicenter Phase 3 trials are underway to study repeated PDT treatments, applied every three months. The interim data look promising in terms of decreased rates of moderate vision loss (TAP Study Group (1999) ARCHIVES OF OPHTHALMOLOGY 117: 1329–45). The necessity for repeated PDT treatments can nevertheless be expected to lead to cumulative damage to the retinal pigment epithelium (RPE) and choriocapillaris, which may lead to progressive treatment-related vision loss.
Therefore, there is still a need for improved PDT-based methods that increase the efficacy and selectivity of treatment, and which reduce or delay a recurrence of the disorder.